EP3677260A1 - Dosage regimen for a s1p receptor agonist - Google Patents

Dosage regimen for a s1p receptor agonist Download PDF

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Publication number
EP3677260A1
EP3677260A1 EP20160225.7A EP20160225A EP3677260A1 EP 3677260 A1 EP3677260 A1 EP 3677260A1 EP 20160225 A EP20160225 A EP 20160225A EP 3677260 A1 EP3677260 A1 EP 3677260A1
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Prior art keywords
dosage
agonist
treatment
receptor modulator
days
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English (en)
French (fr)
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Robert Schmouder
Thomas Dumortier
Olivier David
Michael Looby
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Novartis AG
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/10—Phosphatides, e.g. lecithin

Definitions

  • the present invention relates to a dosage regimen of a S1P receptor modulator or agonist. More specifically, the present invention relates to a dosage regimen for the treatment of patients suffering from autoimmune diseases or disorders, such as, for example, multiple sclerosis with a S1P receptor modulator or agonist.
  • S1P receptor modulators or agonists are compounds which signal as agonists at one or more sphingosine-1 phosphate receptors, for example, S1P1 to S1P8.
  • the binding of an agonist to a S1P receptor may, for example, result in the dissociation of intracellular heterotrimeric G-proteins into Ga-GTP and Gâ ⁇ -GTP, and/or the increased phosphorylation of the agonist-occupied receptor, and/or the activation of downstream signaling pathways/kinases.
  • S1P receptor modulators or agonists are useful therapeutic compounds for the treatment of various conditions in mammals, especially in human beings.
  • the efficacy of S1P receptor modulators or agonists in the prevention of transplant rejection has been demonstrated in rat (skin, heart, liver, small bowel), dog (kidney), and monkey (kidney) models.
  • S1P receptor modulators or agonists are also useful for the treatment of inflammatory and autoimmune diseases.
  • the efficacy of the S1P receptor agonist FTY720 in the treatment of multiple sclerosis has been demonstrated in humans (as described in, for example, " FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis".
  • Multiple sclerosis is the chief cause of neurological disability in young adults and the most common demyelinating disorder of the central nervous system.
  • therapies such as interferon-â and glatiramer acetate, only have modest efficacy and therefore demonstrate only marginal effects on the progression of the disease.
  • these biological agents are administered parenterally and are associated with some adverse effects such as, for example, localized reactions at the injection site and pyretic symptoms. Therefore, there is a strong medical need for an effective oral treatment for multiple sclerosis.
  • S1P receptor modulators or agonists may produce a negative chronotropic effect, i.e. they may reduce the cardiac rhythm, as described e.g. in " FTY720: Placebo-Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects", Robert Schmouder, Denise Serra, Yibin Wang, John M. Kovarik, John DiMarco, Thomas L. Hunt and Marie-Claude Bastien. J. Clin. Pharmacol. 2006; 46; 895 .
  • Administration of 1.25 mg of FTY720 may induce a decrease in heart rate of approximately 8 beats/min (BPM).
  • the S1P modulator or agonist therapy may have to be initiated under close medical supervision in order to check that the cardiac rhythm is maintained at an acceptable level. This may involve the hospitalisation of patients, which makes the treatment more expensive and complicated.
  • Administering a S1P receptor agonist or modulator according to the specific dosage regimen of the present invention may also significantly reduce or even completely eliminate the risks that the patients taken the S1P receptor agonist or modulator suffer from atrio-ventricular (AV) blocks or heart pause.
  • AV atrio-ventricular
  • the specific dosage regimen of the present invention permits to administer a S1P receptor agonist or modulator to categories of patients for which the ratio risk/benefit may otherwise be less favourable.
  • patients are for example patients susceptible to or suffering from heart failure or arrythmias, patients with high grade atrio-ventricular blocks or sick sinus syndrome, patients with a history of syncopal episodes, or patients under beta blockers or anti-arrhythmic treatment, such as patients under anti-arrhythmic drugs; or patients that have undergone an interruption or treatment holiday in the maintenance dosage regime e.g. a holiday of greater than 4 days, greater than 6, 8, 10, 12 or 14 days.
  • the dosage regimen of the present invention is a regimen for the initiation of S1P receptor modulator or agonist therapy, which enables the standard daily therapeutic dosage range of the S1P receptor to be achieved with minimal negative chronotropic effects and/or the AV block effects possibly associated with S1P receptor modulator therapy.
  • Preferred S1P receptor agonists or modulators are, for example, compounds which, in addition to their S1P binding properties, also have accelerating lymphocyte homing properties.
  • the compounds may elicit lymphopenia resulting from a redistribution of lymphocytes from the circulation to the secondary lymphatic tissue, which is preferably reversible, without evoking a generalized immunosuppression.
  • naive cells are sequestered and CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's patches (PP).
  • S1P receptor modulators or agonists are typically sphingosine analogues, such as 2-substituted 2-amino- propane-1,3-diol or 2-amino-propanol derivatives.
  • the S1P receptor modulator or agonist is a compound comprising a group of formula X wherein Z is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, phenyl substituted by OH, C 1-6 alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C 3-8 cycloalkyl, phenyl and phenyl substituted by OH, or CH 2 -R 4z wherein R 4z is OH, acyloxy or a residue of formula (a)
  • the group of formula X is a functional group which is attached as a terminal group to a moiety which may be hydrophilic or lipophilic and comprise one or more aliphatic, alicyclic, aromatic and/or heterocyclic residues.
  • the resultant molecule functions as a modulator/agonist at one of more sphingosine-1-phosphate receptors.
  • At least one of Z and R 1z is or comprises a residue of formula (a).
  • S1P receptor agonists or modulators examples include:
  • Examples of pharmaceutically acceptable salts of the compounds of the formulae I, IIa or IIb include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine.
  • the compounds and salts of the combination of the present invention encompass hydrate and solvate forms.
  • the carbon chain as R 1 is substituted in the compounds of formula I, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy.
  • the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted.
  • the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.
  • Preferred compounds of formula I are those wherein R 1 is C 13-20 alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R 1 is phenylalkyl substituted by C 6-14 -alkyl chain optionally substituted by halogen and the alkyl moiety is a C 1-6 alkyl optionally substituted by hydroxy. More preferably, R 1 is phenyl-C 1-6 alkyl substituted on the phenyl by a straight or branched, preferably straight, C 6-14 alkyl chain. The C 6-14 alkyl chain may be in ortho, meta or para, preferably in para.
  • each of R 2 to R 5 is H.
  • a preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol.
  • a particularly preferred S1P receptor agonist of formula I is FTY720, i.e. 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), or a prodrug thereof.
  • the agonist of formula I is FTY720 hydrochloride, as shown below:
  • a preferred compound of formula Ila is the FTY720-phosphate (Compound B) (R 2a is H, R 3a is OH, X a is O, R 1a and R 1b are OH).
  • a preferred compound of formula IIb is the Compound C-phosphate (R 2a is H, R 3b is OH, X a is O, R 1a and R 1b are OH, Y a is O and R 4a is heptyl).
  • a S1P receptor agonist or modulator for use in the dosage regimen of the invention may also be selective for the S1P 1 receptor.
  • the 35 S-GTP ⁇ S binding assay is described in WO03/097028 and follows the following protocol: GTPyS binding experiments are performed as described by DS. Im et al., Mol. Pharmacol. 2000; 57:753 .
  • Ligand-mediated GTP?S binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCl, 10 MgCl 2 , pH 7.5) using 25 ⁇ g of a membrane preparation from transiently transfected HEK293 cells.
  • Ligand is added to membranes in the presence of 10 ⁇ M GDP and 0.1 nM [ 35 S]GTP ⁇ S (1200 Ci/mmol) and incubated at 30°C for 30 min.
  • Bound GTPyS is separated from unbound using the Brandel harvester (Gaithersburg, MD) and counted with a liquid scintillation counter.
  • the present invention provides a novel dosage regimen which is adapted to minimize the negative chronotropic effects and/or the AV block effects possibly associated with S1P receptor modulator or agonist therapy.
  • Heart effects include AV blocks, which include first degree AV blocks (e.g. PR intervals greater then 0.2 seconds) and second degree AV blocks e.g. first degree AV blocks.
  • Heart effects include heart pauses e.g. heart pauses greater than 2 seconds.
  • a S1P receptor modulator or agonist in the manufacture of a medication, whereby said medication is administered in such a way that during the initial period of treatment the dosage is lower than the standard daily dosage and the dosage is increased, optionally stepwise, or only once, until the standard daily dosage dose is reached. Thereafter the treatment is preferably continued with the standard daily dosage of said S1P receptor modulator or agonist.
  • the medication is administered in a dosage regimen such that daily decrease in heart rate (e.g. average or minimum daily heart rate) is acceptable or clinically not significant, or that the sinus rhythm of the patient is normal.
  • daily decrease in heart rate e.g. average or minimum daily heart rate
  • the daily decrease in heart rate may be less than about 4bpm, e.g. less than about 3 bpm or less than about 2bpm.
  • normal sinus rhythm refers to the sinus rhythm of the patient when not undergoing treatment. The evaluation of normal sinus rhythm is within the ability of a physician. A normal sinus rhythm will generally give rise to a heart rate in the range from 60-100 bpm.
  • the dosage is lower than the standard daily dosage and the dosage is increased, optionally stepwise, or only once, until the standard daily dosage dose is reached. Thereafter the treatment is preferably continued with the standard daily dosage of said S1P receptor modulator or agonist.
  • the "initial period of treatment” refers to the period during which the S1P receptor modulator or agonist is administered at a dosage lower than the standard daily dosage.
  • the “initial period of treatment” starts with the first administration of the S1P receptor modulator or agonist.
  • the duration of the initial period of treatment may vary.
  • the initial period of treatment is up to 10 days, e.g. about a week.
  • the initial period of treatment is 5 to 14 days, e.g. 4 to 12 days.
  • the initial period of treatment is 7 to 10 days.
  • the initial period of treatment is 4 to 7 days.
  • the initial period of treatment is selected from 10 days, or 9 days, or 8 days, or 7 days, or 6 days, or 5 days, or 4 days.
  • standard daily dosage refers to the required daily maintenance dose of the drug which is given to the patients for treating or preventing the disease to be treated or prevented.
  • the standard daily dosage corresponds to the therapeutically effective dosage.
  • the therapeutically effective dosage refers to the dosage of the S1P receptor modulator or agonist which is necessary to effectively treat the intended disease or condition (i.e. so that the subject shows reduced signs or symptoms of rebound of the disease to be treated or prevented, and preferably no signs and symptoms at all).
  • the S1P receptor modulator or agonist may be administered at a dosage e.g. up to 10-fold less, e.g. up to 8-fold less, e.g. up to 4-fold less, than the standard daily maintenance dose, e.g. than the therapeutic dose.
  • an S1P receptor modulator or agonist in the manufacture of a medication, whereby said medication is administered in such a way that during the initial period of treatment (e.g. the first 10 days of treatment, e.g. the first week of treatment, or the first 5 to 14 days of treatment, the first 4 to 12 days of treatment, or the first 7 to 10 days of treatment, or the first 10, 9, 8, 7, 6 , 5 or 4 days of treatment), the dosage of said S1P receptor modulator or agonist is given at a dosage of up to 10-fold less, e.g. up to 5-fold less, than the standard daily dose, e.g. the therapeutic dose.
  • the dose is then raised stepwise up to the standard daily dose, e.g. the therapeutic dose, during the initial period of treatment as herein above defined.
  • Preferred medications comprise medication for patients suffering from chronic long term diseases, such as autoimmune diseases, e.g. multiple sclerosis, Polymyositis, lupus nephritis, rheumatoid arthritis, inflammatory bowel diseases or psoriasis.
  • medications are medications for patients suffering from multiple sclerosis, for example relapse remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS), e.g. for patients suffering from RRMS.
  • RRMS relapse remitting multiple sclerosis
  • PPMS primary progressive multiple sclerosis
  • the dosage regimen of the present invention is particularly useful for treating patents at risk of cardiac side effects, for example patients at risk of heart failure, arrythmias, patients with high grade atrio-ventricular blocks or sick sinus syndrome, patients with a history of syncopal episodes, or patients requiring or under beta blockers, or patients requiring or under anti-arrhythmic treatment, such as patients under treatment with Class Ia (e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol).
  • Class Ia e.g. quinidine, procainamide
  • Class III anti-arrhythmic drugs e.g., amiodarone, sotalol
  • an example of standard daily dosage may be a daily dosage of up to 5mg, for example, the dosage may be between 0.5 and 5 mg, e.g. between 0.5 and 2mg. In a specific embodiment, the standard daily dosage is about 1.25 mg. In another embodiment, the standard daily dosage is about 0.5 mg.
  • the dosage of the S1P receptor modulator or agonist during the initial period of treatment is increased stepwise in defined increments up to the standard daily dosage of the S1P receptor modulator or agonist.
  • the dosage of said S1P receptor modulator or agonist during the initial period of treatment as hereinabove defined, e.g. during the initial 10 days, e.g. 1 to 9 days, e.g. first week of treatment is increased in increments of about 1.5- to about 3.5-fold, for example from 2 to 3-fold, for example 2-fold, for example about 1.5-fold.
  • the dose may be about 10-fold less, or about 8-fold less, or about 5-fold less, or about 3-fold less, about 2-fold less or about 1.5-fold less than the standard daily dosage, e.g. than the therapeutic dose.
  • the initial dosage administered during the initial period of treatment is about 10-fold less than the standard daily dosage, e.g. than the therapeutic dose, and is then increased in increments to a daily dosage which is about 5 fold less than the standard daily dosage and then about 2.5 fold less than the standard daily dosage. Thereafter, treatment is commenced at the standard daily dosage.
  • the initial dosage administered during the initial period of treatment as hereinabove defined is about 4-fold less than the standard daily dosage, e.g. than the therapeutic dose, and is then increased in increments to a daily dosage which is about 2 fold less than the standard daily dosage. Thereafter, treatment is commenced at the standard daily dosage.
  • each subsequent incremental dosage increase is administered for 1, 2, 3, 4 or 5 days.
  • each subsequent incremental dosage increase is administered for 2 or 3 days.
  • the same initial dosage may be given during the first 1 to 7 days, e.g. for 2 to 5 days, e.g. the first 2 days, before the dosage is further increased, e.g. up to the standard daily dosage in one or more increments.
  • One or more dosage increases may be performed until the standard daily dosage is given.
  • 1 to 10 dosage increases e.g. up to 8 dosage increases, e.g. up to 6 dosage increases, e.g. up to 5 dosage increases, up to 4 dosage increases, up to 3 dosage increases
  • 1 to 10 dosage increases e.g. up to 8 dosage increases, e.g. up to 6 dosage increases, e.g. up to 5 dosage increases, up to 4 dosage increases, up to 3 dosage increases
  • 1 to 10 dosage increases e.g. up to 8 dosage increases, e.g. up to 6 dosage increases, e.g. up to 5 dosage increases, up to 4 dosage increases, up to 3 dosage increases
  • 1 to 10 dosage increases e.g. 1 to 8 e.g. 1 to 3, e.g. 2 to 8, e.g. 3 to 6 dosage increases may be given.
  • the daily dosage is governed by a Fibonacci series i.e. the dosage given on a specific day is the sum of the dosages on the previous two days.
  • the dosage on a given day may be the sum of the dosages on the two previous days ⁇ 40%, for example ⁇ 30%, for example ⁇ 20% or ⁇ 10%.
  • the first dosage increase may occur on day 2 to day 5, e.g. day 2 to day 4, e.g. day 2, day 3, day 4 or day 5, after the first administration.
  • the second dosage increase if any, may occur on day 4 to 10, e.g. day 4 to 6, e.g. day 5, after the first administration.
  • the third dosage increase if any, may occur on day 6 to 10, e.g. day 6 or 7, after first administration.
  • only one or two dosage increase occur before the standard daily dosage, e.g. the therapeutic dosage, is given.
  • the S1P receptor agonist is Compound A or Compound B, e.g. FTY720, or a pharmaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720.
  • the highest initial dosage of the S1P receptor modulator or agonist is between 0.01 mg and 0.30 mg, e.g. between 0.125 and 0.25mg, preferably 0.125mg or 0.1mg.
  • a particularly preferred dosage range of the S1P receptor modulator or agonist e.g. Compound A,Compound B or a salt thereof, e.g. the hydrochloride salt of FTY720
  • the initial period of treatment as hereinabove defined is e.g. 0.125-1.25 mg, or 0.1-0.5 mg, or 0.125-0.5 mg, or 0.25-0.5 mg.
  • it may be a regimen of 0.125mg/0.25mg/0.5mg, respectively, during the initial period of e.g. up to the first 10 days. Thereafter the treatment is continued with the standard daily dosage, e.g. a dosage of 1.25 mg.
  • This regimen is particularly adapted for compound A.
  • it may be a regimen comprising an initial daily dose of 0.125mg which is subsequently increased to a daily dose of 0.25mg during the initial period of treatment. Thereafter the treatment is continued with the standard daily dosage, e.g. 0.5mg. Again, this regimen is particularly adapted for compound A.
  • the present invention also provides:
  • the daily dosage of the S1P receptor modulator or agonist is lower than the standard dosage, and is raised stepwise up to 6 times, e.g. three times, e.g. two times,up to the standard daily dosage of said S1P receptor modulator or agonist and thereafter the treatment is continued with the standard daily dosage of said S1P receptor modulator or agonist.
  • a S1P receptor modulator or agonist e.g. compound A, B or a salt or prodrug thereof
  • the improvement is due to said S1P receptor modulator or agonist is administered in such a way that during the initial period of treatment, e.g. the initial 10 days, e.g. 9 days, e.g. first week, of treatment, the dosage is lower than the standard dosage, e.g. 10-fold less, e.g. 5-fold less, e.g. 4 fold-less, e.g. 2 to 3 fold-less, e.g. 2 fold-less, than the standard daily dosage, and is increased, optionally stepwise, up to the standard daily dosage. Thereafter the treatment is continued with the standard effective daily dosage.
  • the kit may comprise just one low dose unit of medication at a dosage strength corresponding to an initial dosage of the S1P receptor modulator or agonist.
  • a patient may then take one unit of the low dose medication for a specified number of days and then, optionally, two or more units per day on subsequent days until therapy is commenced with a unit of medication that comprises the standard daily dose of the S1P receptor agonist.
  • the kit may comprise a number of low-dose units of medication with a range of dosage strengths so that the patient can be administered one dosage unit per day, but the amount of S1P receptor modulator or agonist administered can be titrated upwards until therapy commences at the standard daily dosage.
  • the daily units of said S1P receptor modulator or agonist may be of about 1/10, about 1/5 and about 1/2.5; or about 1/5 and about 1/2.5, of the standard dose of said S1P receptor modulator or agonist, respectively.
  • the daily units of said S1P receptor modulator or agonist may be of about 1/8, about 1/4 and about 1 ⁇ 2; or about 1/4 and about 1 ⁇ 2, of the standard dose of said S1P receptor modulator or agonist, respectively.
  • the kit may further comprise units for the standard daily dosage of the S1P receptor modulator or agonist, e.g. compound A, B, or a salt or prodrug thereof.
  • the kit may also contain instructions for use.
  • the regimen of S1P receptor modulator or agonist which is administered to the subject according to the invention may be given either during at the beginning of the disease therapy, e.g. during the initial 10 days, or after an interruption of S1P receptor modulator or agonist therapy, for example an interruption of more than 10 days, more than 12 days, e.g. more than 14 days.
  • the present invention relates to a daily dosage of the S1P receptor modulator or agonist, e.g. compound A (or B), or, in each case, a pharmaceutically acceptable salt, e.g. a hydrochloride salt, thereof, is selected from any one of the following: about 1.25 mg or less, e.g. is from about 1.25 mg to about. 0.01 mg, e.g. is 1.25 mg, e.g. 1.20 mg, e.g. 1.15 mg, e.g. 1.10 mg, e.g. 1.05mg, e.g. 1.00 mg, e.g. 0.95mg, e.g. 0.90 mg, e.g. 0.85mg, e.g.
  • 0.80 mg e.g. 0.75 mg, e.g. 0.70 mg, e.g. 0.65 mg, e.g. 0.60 mg, e.g. 0.55 mg, e.g. 0.50 mg, e.g. 0.45 mg, e.g. 0.40 mg, e.g. 0.35 mg, e.g. 0.30 mg, e.g. 0.25mg, e.g. 0.20 mg, e.g. 0.15 mg, e.g. 0.125 mg, e.g. 0.12 mg, e.g. 0.115 mg, e.g. 0.11mg, e.g. 105 mg, e.g. 0.1 mg, e.g. 0.055 mg, e.g.
  • 0.05 mg e.g. 0.045 mg, e.g. 0.04 mg, e.g. 0.035 mg, e.g. 0.03 mg, e.g. 0.025 mg, e.g. 0.02 mg, e.g. 0.01 mg.
  • the daily dosage of the compound e.g. FTY720 or FTY720 phosphate, is 0.5mg.
  • the present invention therefore includes, in a further aspect, the above mentioned daily dosages of FTY720, FTY720 phosphate or, in each case, a pharmaceutically acceptable salt, e.g. a hydrochloride salt, thereof.
  • the invention relates to the above mentioned daily dosages of FTY720 phosphate or the hydrochloride salt of FTY720.
  • the daily dosage of FTY720, FTY720 phosphate or, in each case, a pharmaceutically acceptable salt, e.g. a hydrochloride salt is about 0.5 mg, or about 0.25mg, or about 0.125 mg, or about 0.1mg.
  • a pharmaceutically acceptable salt e.g. a hydrochloride salt
  • the daily dosage of FTY720 phosphate or the hydrochloride salt of FTY720 is about 0.5 mg, or about 0.25mg, or about 0.125 mg, or about 0.1mg.
  • S1P receptor modulator or agonist dosage regimen in treating diseases and conditions as hereinabove specified may be demonstrated in standard animal or clinical tests, e.g. in accordance with the methods described hereinafter.
  • Figure 1 shows the mean (+/- standard error) daily average heart rate on days 1 to 9 for the treatment regimen groups described in the Example below.
  • the x-axis is shows the study days and the Y-axis shows the mean (+/-SE) daily average heart rate (beats per minute (BPM)).
  • a single-center, double-blind, placebo-controlled, dose titration, once-daily, multiple-oral-dose clinical study in healthy subjects was conducted to evaluate the effect of a dosage regimen of FTY720 according to the present invention.
  • Each subject participated in a screening period of maximal 21 days, a baseline period (Day-1), a 9-day dose-administration period, and clinical study completion assessments on Day 10.
  • Subjects were assigned to one of the three groups (dose titration regimen group, placebo control group, or active control group) and received the once daily dose in a double-blinded manner (Table 1).
  • baseline assessments including 24 hour holter monitoring and telemetry assessments.
  • Pharmacodynamic and safety assessments are performed up to 24 hours post last dose. Heart rate is monitored via telemetry on Day -1 through Day 10, 24 hour after the last dosing. Heart rhythm is assessed via 24hr continuous holter monitoring on Day -1, Day 1, and Day 9. For each dosing for each subject, the drug is administered as closely as practically possible to the time administered on Day -1.
  • Safety assessments includes physical examinations, vital signs and body measurements, 12-lead ECG evaluations, standard clinical laboratory evaluations hematology, blood chemistry, urinalysis, adverse event and serious adverse event monitoring. Systolic and diastolic blood pressure and pulse are measured after the subject has rested quietly in the sitting position for at least 3 minutes. Blood pressure is measured at the same arm on each occasion.
  • Standard 12-lead ECGs are recorded at Screening, baseline, 4 hours post-dose on Day 1 and Day 8, and at Study Completion.
  • the variables recorded are: date and time of ECG, heart rate, PR interval, QT interval (uncorrected), QTcB, QRS duration.
  • the overall interpretation is collected with a Yes/No statement to confirm if any clinically relevant abnormalities are present, which needs to be specified further.
  • Subjects remain on continuous telemetry, starting before breakfast on Day -1 and proceeding throughout the administration period up to Day 10 (24 hour after the last dose). Over this ten day duration of continuous heart rate collection for each subject, one heart rate value is obtained every minute ('minute unit heart rate'), representing the average heart rate value over that minute.
  • the heart rate database for each subject contains approximately 14,400 data points (10 days x 24 hr x 60 min).
  • 24-hour continuous Holter-ECG data are captured via a digital Holter monitor (12-lead, on Days -1, 1, 6, and 8), and transferred for interpretation and reporting.
  • Holter monitoring starts approximately at 7:00 and the time of dose administration is regarded as the time "0 hours”.
  • Holter "cuts" are derived from the dataset at 1 hour intervals starting from Day -1 and continuing for 24 hours or the end of the cleaned Holter monitoring dataset.
  • arrhythmia monitoring includes the frequency and duration of sinus pauses (>2 sec and > 3 sec) and atrio-ventricular blocks. Frequency and duration of atrial and ventricular ectopy and sinus rhythm are also recorded.
  • the daily chronotropic effect is defined as the percent decrease in HR min (minimum heart rate) between two consecutive days. It is calculated on days 1 to 9.
  • FIG. 1 The results are shown in Figure 1 .
  • daily average heart rate varies by approximately 5 BPM (beats per min) over the course of the study with a trend for heart rate to increase approximately 3-4 BPM from Day -1 to Day 2.
  • the FTY720 1.25 mg treatment group manifestes a significant decrease in heart rate of approximately 8 BPM from Day -1 to Day 1 and an additional decrease in heart rate approximately 3 BPM from Day 1 to Day 2.
  • the FTY720 titration group manifestes a gradual decrease in heart rate of approximately 1-2 BPM per day over the course of eight day course of the dose titration. The initiation of the 1.25 mg FTY720 on Day 8 does not result in dip in heart rate compared to the preceding days.

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Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR070842A1 (es) * 2008-03-17 2010-05-05 Actelion Pharmaceuticals Ltd Regimen de dosificacion para un agonista de receptor selectivo de s1p1
EP4098256A1 (en) 2008-12-22 2022-12-07 Novartis AG Dosage regimen for a s1p receptor agonist
WO2011041146A2 (en) 2009-09-29 2011-04-07 Novartis Ag Dosage regimen of an s1p receptor modulator
US20110124605A1 (en) * 2009-11-20 2011-05-26 Shreeram Aradhye Use of an S1P Receptor Agonist
CN103221391B (zh) 2010-01-27 2018-07-06 艾尼纳制药公司 (R)-2-(7-(4-环戊基-3-(三氟甲基)苄基氧基)-1,2,3,4-四氢环戊二烯并[b]吲哚-3-基)乙酸及其盐的制备方法
MX2012012925A (es) * 2010-05-06 2012-12-17 Novartis Ag Regimen de dosificacion de derivados de sulfuro de diarilo.
EP2455080A1 (en) * 2010-11-23 2012-05-23 Almirall, S.A. S1P1 receptor agonists for use in the treatment of multiple sclerosis
FR2968556B1 (fr) 2010-12-13 2013-12-27 Centre Nat Rech Scient Inhibiteurs des infections a vih et leurs utilisations
EP2675893B1 (en) * 2011-02-18 2019-01-09 The Scripps Research Institute Directed differentiation of oligodendrocyte precursor cells to a myelinating cell fate
AR085749A1 (es) 2011-04-01 2013-10-23 Novartis Ag Formulaciones
WO2012162392A1 (en) * 2011-05-23 2012-11-29 Timothy Hla Endothelium protective materials and methods of use
TW201320994A (zh) 2011-10-11 2013-06-01 Novartis Ag 投藥療程
EP2885266B1 (en) 2012-08-17 2020-03-18 Actelion Pharmaceuticals Ltd Process for the preparation of (2z,5z)-5-(3-chloro-4-((r)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one and intermediate used in said process
JP6542678B2 (ja) * 2013-03-06 2019-07-10 アコーダ セラピューティクス インコーポレイテッド 心不全の治療または予防のためのニューレグリンまたはその断片の治療的投与の方法
WO2015053878A1 (en) 2013-10-11 2015-04-16 Teikoku Pharma Usa, Inc. Topical sphingosine-1-phosphate receptor agonist formulations and methods of using the same
US10675254B2 (en) 2013-10-11 2020-06-09 Teikoku Seiyaku Co., Ltd. Sphingosine-1-phosphate receptor agonist iontophoretic devices and methods of using the same
CA2943598C (en) * 2014-04-10 2023-03-07 Novartis Ag S1p modulator immediate release dosage regimen
UA122064C2 (uk) 2014-12-11 2020-09-10 Актеліон Фармасьютікалз Лтд Схема дозування для селективного агоніста рецептора s1p1
CN107405332A (zh) * 2015-01-06 2017-11-28 艾尼纳制药公司 治疗与s1p1受体有关的病症的方法
CA2973540A1 (en) 2015-02-26 2016-09-01 Novartis Ag Treatment of autoimmune disease in a patient receiving additionally a beta-blocker
US10301262B2 (en) 2015-06-22 2019-05-28 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compund1) for use in SIPI receptor-associated disorders
EP3582772A1 (en) 2017-02-16 2019-12-25 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
MA47503A (fr) 2017-02-16 2021-04-21 Arena Pharm Inc Composés et méthodes pour le traitement de maladies inflammatoires chroniques de l'intestin avec manifestations extra-intestinales
EP4051250A1 (en) 2019-10-31 2022-09-07 Idorsia Pharmaceuticals Ltd Combination of a cxcr7 antagonist with an s1p1 receptor modulator
WO2021158838A1 (en) 2020-02-07 2021-08-12 Argentum Pharmaceuticals Llc Dosage regimen of an s1p receptor modulator
WO2021158848A1 (en) * 2020-02-07 2021-08-12 Argentum Pharmaceuticals Llc Dosage regimen of an s1p receptor agonist
CN113332435B (zh) * 2021-06-18 2022-10-18 广州中医药大学(广州中医药研究院) 鞘氨醇-1-磷酸4受体激动剂及其与真武汤联合在制备治疗慢性肾小球肾炎药物中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0627406A1 (en) 1992-10-21 1994-12-07 Yoshitomi Pharmaceutical Industries, Ltd. 2-amino-1,3-propanediol compound and immunosuppressant
WO2002018395A1 (en) 2000-08-31 2002-03-07 Merck & Co., Inc. Phosphate derivatives as immunoregulatory agents
WO2003097028A1 (en) 2002-05-16 2003-11-27 Novartis Ag Use of edg receptor binding agents in cancer
WO2009115954A1 (en) * 2008-03-17 2009-09-24 Actelion Pharmaceuticals Ltd Dosing regimen for a selective s1p1 receptor agonist
WO2009155475A1 (en) * 2008-06-20 2009-12-23 Novartis Ag Paediatric compositions for treating1 multiple sclerosis

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025553A2 (en) * 2003-09-12 2005-03-24 Neuronova Ab Treatment of disorders of nervous systemsystem with fty720
US20060002999A1 (en) * 2004-06-17 2006-01-05 Forest Laboratories, Inc. Immediate release formulations of 1-aminocyclohexane compounds, memantine and neramexane
SG158096A1 (en) * 2004-11-29 2010-01-29 Novartis Ag Dosage regimen of an s1p receptor agonist
EP1688141A1 (en) * 2005-01-31 2006-08-09 elbion AG The use of flupirtine for the treatment of overactive bladder and associated diseases, and for the treatment of irritable bowel syndrome
EP1850689A4 (en) * 2005-02-10 2013-05-22 G I View Ltd TECHNIQUES FOR DISPLACING A GASTROINTESTINAL TOOL EQUIPPED WITH A GUIDING ELEMENT
EP3120833A1 (en) * 2007-10-12 2017-01-25 Novartis Ag Compositions comprising sphingosine 1 phosphate (s1p) receptor modulators
KR101660555B1 (ko) * 2008-12-22 2016-09-27 노파르티스 아게 Ｓ１ｐ 수용체 효능제의 투여 요법
EP4098256A1 (en) 2008-12-22 2022-12-07 Novartis AG Dosage regimen for a s1p receptor agonist

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0627406A1 (en) 1992-10-21 1994-12-07 Yoshitomi Pharmaceutical Industries, Ltd. 2-amino-1,3-propanediol compound and immunosuppressant
WO2002018395A1 (en) 2000-08-31 2002-03-07 Merck & Co., Inc. Phosphate derivatives as immunoregulatory agents
WO2003097028A1 (en) 2002-05-16 2003-11-27 Novartis Ag Use of edg receptor binding agents in cancer
WO2009115954A1 (en) * 2008-03-17 2009-09-24 Actelion Pharmaceuticals Ltd Dosing regimen for a selective s1p1 receptor agonist
WO2009155475A1 (en) * 2008-06-20 2009-12-23 Novartis Ag Paediatric compositions for treating1 multiple sclerosis

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BUDDE K ET AL: "First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients", JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 13, no. 4, 1 January 2002 (2002-01-01), pages 1073 - 1083, XP003016978, ISSN: 1046-6673 *
DS. IM ET AL., MOL. PHARMACOL., vol. 57, 2000, pages 753
KAPPOS LANTEL JCOMI GMONTALBAN XO'CONNOR PPOLMAN CHHAAS TKORN AAKARLSSON GRADUE EW: "Oral fingolimod (FTY720) for relapsing multiple sclerosis", N ENGL J MED., vol. 355, no. 11, 14 September 2006 (2006-09-14), pages 1124 - 40, XP009072986, DOI: 10.1056/NEJMoa052643
KOYRAKH LEV ET AL: "The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I.", March 2005, AMERICAN JOURNAL OF TRANSPLANTATION : OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF TRANSPLANTATION AND THE AMERICAN SOCIETY OF TRANSPLANT SURGEONS MAR 2005, VOL. 5, NR. 3, PAGE(S) 529 - 536, ISSN: 1600-6135, XP002562406 *
MEHLING MBRINKMANN VANTEL JBAR-OR AGOEBELS NVEDRINE CKRISTOFIC CKUHLE JLINDBERG RLKAPPOS L: "FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis", NEUROLOGY, vol. 71, no. 16, 14 October 2008 (2008-10-14), pages 1261 - 7, XP009165260, DOI: 10.1212/01.wnl.0000327609.57688.ea
ROBERT SCHMOUDERDENISE SERRAYIBIN WANGJOHN M. KOVARIKJOHN DIMARCOTHOMAS L. HUNTMARIE-CLAUDE BASTIEN: "FTY720: Placebo-Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects", J. CLIN. PHARMACOL., vol. 46, 2006, pages 895, XP008107801, DOI: 10.1177/0091270006289853
SCHMOULDER R., ET AL.: "Multiple Sclerosis", vol. 14, part Abst P507 17 September 2008, SAGE, London, article ORAL FINGOLIMOD (FTY720), 0.5 OR 1.25 MG, FOR 14 DAYS HAS NO EFFECT ON CARDIAC FUNCTION: "World Congresson Treatment and Research on Multiple Sclerosis", pages: S177, XP009127649 *

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Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR